The present invention relates to a single drug delivery unit suitable for oral administration containing at least two distinct drug dosage packages. This multiplex system contains at least two immediate-release compartments substantially enveloped by a scored extended-release compartment. The scored nature of the extended-release *compartment facilitates the separation by the patient of the multiplex drug delivery system into individual drug dosage packages for oral administration of the prescribed dosage. Upon separation, each individual drug dosage package can exhibit an equivalent, and preferably identical, release profile for the active agent as compared to one another and to that of the entire multiplex system. Accordingly, in a preferred embodiment, the separability of the multiplex drug delivery system enables its use throughout the entire course of a varying dosage regimen, and thus, facilitates cost effective patient compliance.
Drug efficacy depends upon the maintenance of the proper therapeutic levels of the drug over the required treatment period. With respect to orally administered drugs, the effectiveness of treatment depends, in part or sometimes in whole, on patient compliance with the prescribed dosage regimen. Particularly where the prescribed dosage increases or decreases during the treatment period, patient compliance can suffer because of the unavailability of, or inconvenience in obtaining, the appropriate dosage of the prescribed medication at different times.
It would therefore be beneficial for patients to have one drug delivery unit that allows patients themselves to regulate the amount of drug to administer. Such a capability would enable patients to use the same drug delivery unit throughout their entire treatment period even where their prescribed dosage changes during that time. Patients in such circumstances would have the convenience and cost effectiveness of obtaining in one unit and at the same time the different dosages of their prescribed drug that would be needed during their treatment period.
A valuable contribution to the art therefore would be the development of a multiplex drug delivery system suitable for oral administration containing at least two immediate-release compartments substantially enveloped by a scored extended-release compartment that facilitates the separation of the multiplex drug delivery system into individual drug dosage packages for oral administration of the prescribed dosage, each of which can exhibit an equivalent, and preferably identical, release profile for the active agent as compared to one another and to that of the entire multiplex system.
Accordingly, an objective of the present invention is a single drug delivery unit suitable for oral administration that patients could separate into individual drug dosage packages. These individual drug dosage packages can exhibit an equivalent, and preferably identical, release profile for the active agent when compared to one another or when compared to the entire, intact multiplex drug delivery system.
The present invention accomplishes this objective through a multiplex drug delivery system suitable for oral administration containing at least two immediate-release compartments. The scored extended-release compartment of the invention allows the separation of the multiplex drug delivery system into individual drug dosage packages for oral administration of the prescribed dosage, each of which can exhibit an equivalent, and preferably identical, release profile for the active agent as compared to one another and to that of the entire multiplex system.
One preferred embodiment of the claimed invention is a multiplex drug delivery system suitable for oral administration comprising at least two immediate-release compartments substantially enveloped by a scored extended-release compartment. The extended-release compartment can comprise a combination of a hydrophobic and a hydrophobic material. In such an embodiment, the hydrophilic polymer(s) dissolves away to weaken the extended-release compartment, while the hydrophobic material retards the water, thus helping to preserve the integrity of the drug delivery system. Where the immediate-release compartments are inert (i.e., do not comprise an active agent), they can facilitate a bursting effect, which can disrupt any remaining integrity of the extended-release compartment.
In another preferred embodiment of the claimed invention, each immediate-release compartment further comprises an effective amount of an active agent, or a pharmaceutically acceptable salt thereof and the scored extended-release compartment further comprises an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, in a compressed blend with the combination of a hydrophilic polymer and a hydrophobic material.
In a further preferred embodiment, each immediate-release compartment further comprises an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, in a compressed blend with a polymer. In one other preferred embodiment, the scored extended-release compartment further comprises an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, in a compressed blend with the combination of a hydrophilic polymer and a hydrophobic material. By varying the composition of the polymer(s) in the immediate-release compartments and/or the relative composition of the hydrophilic polymer and hydrophobic material in the extended-release compartment, the respective time periods for the dissolution of the active agent or the bursting effect can be adjusted.
In a preferred embodiment of the claimed invention, the active agent contained in the multiplex drug delivery system can be a drug. In other embodiments, that drug can be a therapeutic or a prophylactic drug.
In one preferred embodiment of the claimed invention, the drug of the multiplex drug delivery system can be diltiazem, trapidil, urapidil, benziodarone, dipyridamole, isosorbide mononitrate, or lidoflazine. In another embodiment, the drug can be a non-steroidal antiinflammatory drug (NSAID) or steroidal antiinflammatory drug. In an embodiment, the steroidal antiinflammatory drug can be diclofenac sodium, ibuprofen, ketoprofen, diflunisal, piroxicam, motrin, or naproxen. In yet another embodiment, the drug can be acetaminophen, aldosterone, alprenolol, amitryptyline, aspirin, beclomethasone, diproprionate, bromocriptine, butorphanol tartrate, chlormethiazole, chlorpheniramine, chlorpromazine HCl, cimetidine, codeine, cortisone, cyclobenzamine HCl, desmethylimipramine, dextropropoxyphene, dihydroergotamine, diltiazem HCl, dobutamine HCl, domperidone, dopamine HCl, doxepin HCl, epinephrine, ergoloid mesylates, ergotamine tartrate estradiol, ethinylestradiol, flunisolide, fluorouracil, flurazepam HCl, 5-fluoro-21-deoxyuridine, furosemide, glipizide, glyburide, glyceryl trinitrate, guanethidine sulfate, hydralazine HCl, imipramine HCl, indoramin, isoethorine HCl, isoethrine mesylate, isoprenaline, isoproterenol sulfate, isosorbide dinitrate, levallorphan tartrate, levodopa, lidocaine HCl, lignocaine, lorcainide, meperidine HCl, 6-mercaptopurine, metaproterenol sulfate, methoxamine HCl, methylphenidate, methylpreonisolone, methyltestosterone mesylate, metoclopramide, metoprolol tartrate, morphine sulfate, nalbuphine HCl, naloxone HCl, neostigmine, nifedipine, nitrendipine, nitroglycerin, norepinephrine bitartrate, norethindrone, nortriptylene HCl, oxprenolol, oxyphenbutazone, penicillamine, pentazocine HCl, pentazocine lactate, pentobarbital, petnidine, phenacetin, phentolamine HCl, phentolamine mesylate, phenylephrine HCl, phenylephrine bitartrate, phenytoin, pindolal, prazosin, prednisone, progesterone, propoxyphene HCl, propoxyphene napsylate, propranolol HCl, quinidine, reserpine, ritodrine HCl, salicylamide, salbutamol, secobarbital, testosterone, terbutaline, timolol maleate, tolbutamide, or verapamil HCl.
In one other preferred embodiment of the claimed invention, the active agent can preferably be isosorbide-5-mononitrate.
In a preferred embodiment, the active agent of the multiplex drug delivery system can exhibit the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37xc2x0 Cxc2x10.5xc2x0 C. in deionized water at 75 rotations per minute:
from about 0% to about 90% of said active agent is released between 1 hour and 16 hours of measurement in said apparatus; and
from about 0% to about 100% of said active agent is released between 1.5 hours and 28 hours after measurement in said apparatus.
In such a preferred embodiment, the active agent of the multiplex drug delivery system can be isosorbide-5-mononitrate.
In still another preferred embodiment, the active agent of the multiplex drug delivery system can exhibit the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37xc2x0 C.xc2x10.5xc2x0 C. in deionized water at 75 rotations per minute:
from about 10% to about 75% of said active agent is released between 1 hour and 5 hours of measurement in said apparatus; and
no less than about 90% of said active agent is released after 6 hours of measurement in said apparatus.
In one preferred embodiment of the claimed invention, the polymer of the multiplex drug delivery system can be alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, cellulose, pregelatinized starch, sodium alginate, starch, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylates, povidone, shellac, or zein, and preferably hydroxypropyl methylcellulose.
In yet another preferred embodiment, the hydrophilic polymer of the multiplex drug delivery system can be carboxymethylcellulose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, or povidone, and preferably hydroxypropyl methylcellulose.
In a preferred embodiment of the claimed invention, the hydrophobic material of the multiplex drug delivery system can be carnauba wax, ethylcellulose, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, microcrystalline wax, polymethacrylates, or stearic acid, and preferably hydrogenated vegetable oil.
The present invention also accomplishes these and other objectives through a method for preparing a multiplex drug delivery system suitable for oral administration comprising the steps of combining an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, and a polymer to form at least two immediate-release compartments; combining an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, and a hydrophilic polymer and a hydrophobic material to form an extended-release compartment; press coating the extended-release compartment to substantially envelop the at least two immediate-release compartments, and scoring the extended-release compartment such that the immediate-release compartments are separable.
In a preferred embodiment, the method for preparing a multiplex drug delivery system suitable for oral administration can include combining by blending, perforated pan coating, fluidized particle coating, wet granulation, fluid-bed granulation, or dry granulation according to methods recognized in the art.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. The detailed description and the specific examples, however, indicate only preferred embodiments of the invention. Various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.